Social defeat stress results in sustained social avoidance behaviors and other manifestations of depression- like mood disorders. Pretreatment with kappa opioid receptor antagonists or genetic disruption of the dynorphin/? -opioid receptor system (Dyn/KOR) effectively prevents these adverse effects. Stress-induced activation of the Dyn/KOR system has previously been found to encode the dysphoric and anxiogenic effects of stress (as operationally measured by aversion and elevated plus maze behaviors); however, the cellular mechanisms and neuronal circuitry underlying these responses have not yet been defined. In the proposed studies, requesting postdoctoral fellowship support for Dr. Richard Gustin, we ask: 1) Does Social Avoidance following repeated social defeat stress lead to a sustained decrease in social interaction behaviors that can be reversed by subsequent KOR inhibition by the long-acting, non-competitive KOR antagonist, norbinaltorphimine (norBNI)? 2) Which brain regions are necessary targets of Dyn/KOR action that result in the social avoidance and anxiety-like behaviors will be determined by local inhibition of KOR in the dorsal raphe nucleus, nucleus accumbens, and basolateral amygdala? 3) Finally, which brain regions are sufficient to elicit these behaviors will be determined by local injection of lentivirus encoding KOR, selectively restoring receptor expression in the KOR deficient (knockout) mice? Results obtained would help define how KOR activation regulates social avoidance and anxiety-like behaviors following social defeat stress and will help to identify how specific stress-induced behaviors are encoded in the brain. This proposal will lead to a deeper understanding of how stress can produce dysphoric- and anxiety-like behaviors and may help define the therapeutic potential of KOR antagonists in treating the progression of stress-induced depression and related mood disorders. Addressing these questions will provide research training in the development of animal models of human disease, provide additional training in behavioral pharmacological analysis, and enhance research skills in molecular genetic approaches to behavior. The training program outlined in this application would also provide professional development opportunities, enhance presentation and writing skills, and create a strong foundation for a future academic research career. PUBLIC HEALTH RELEVANCE: Exposure to stressors can be extremely debilitating and lead to the manifestation of clinical depression, anxiety, and can exacerbate a number of other psychiatric diseases. We aim to identify how the brain encodes different forms of stress, and how these different stressors can alter brain functions leading to disability. Additionally, our wok has the potential to identify novel therapeutics that may reverse the affects of stress- induced depression and anxiety.